Amyloidosis is the pathological condition defined as the accumulation in tissues of an amyloid protein, usually in an amount sufficient to impair normal organ function. Several different forms of amyloid protein have been defined and at least six different amyloidosis conditions have been described including: amyloidosis related to Alzheimer's disease, amyloidosis related to inflammation, amyloidosis related to adult onset diabetes, amyloidosis related to Gerstmann Straussler Syndrome and Creutzfeldt-Jakob disease, amyloidosis related to familial amyloidotic polyneuropathy, and amyloidosis related to hereditary cerebral hemorrhage with amyloid. Amyloid is also associated with multiple myeloma, Hodgkin's disease, tumors, familial Mediterranean fever as well as generally in aging and other familial forms.
Amyloidosis generally manifests itself as the deposition and accumulation of an amyloid protein in tissues in the form of fine fibrils thereby forming histologic entities such as plaques, or "amyloid tumors". Although amyloids are classified by type of protein, two major clinical forms of amyloidosis are recognized. Primary amyloidosis is defined as amyloidosis where there is no associated disease; secondary or acquired amyloidosis is amyloidosis associated with chronic diseases such as infectious or inflammatory diseases.
In primary amyloidosis, amyloid fibril deposits or "amyloid tumors" can be found in all of the various organs and tissues of the body. Depending on their localization, fibril deposits of primary amyloidosis determine the severity of the implications associated with the condition.
In secondary amyloidosis, the occurrence of amyloid fibril deposits can take place throughout the body in all organs and tissues. In some cases, the amyloid is found associated with only one organ. For example: in Alzheimer's disease-related amyloidosis, amyloid plaques are primarily detected in brain; in amyloidosis associated with adult onset diabetes mellitus, amyloid deposits are often localized only in the pancreas. Nevertheless, amyloid deposits are often found throughout the body in secondary amyloidosis. In particular, in amyloidosis associated with tumors, the occurrences of amyloid deposits are found in nontumourous organs as well as in areas where malignancies are present.
Amyloidosis can only be diagnosed by biopsy. However, the appearance of various symptoms and signs described above lead one to suspect the presence of amyloidosis either as a primary or secondary form.
Local amyloid deposits can be removed without recurrence. However, the occurrence of amyloid deposits in various organs can cause severe problems in the normal functioning of the affected organs. Myocardial amyloidosis is a common cause of death primarily due to arrhythmias or intractable cardiac failure. All forms of renal amyloidosis carry a poor prognosis. Amyloidosis associated with malignancies have the poorest prognosis. In the case of Alzheimer's disease, it is believed that the severity of the disease itself may be reduced by the elimination or slowing of the progression of amyloidosis localized in brain tissue. In some secondary amyloidosis, successful treatment of the underlying disease can reduce or eliminate the presence of amyloidosis.
Treatment for primary amyloidosis is currently directed at controlling the symptoms which are caused by the lesions. Similarly, treatment in secondary amyloidosis attempts to alleviate the problems caused by the lesions as well as treatment of the underlying disease. There is, however, no therapy to reduce or eliminate amyloid deposits. Furthermore, there are currently no assays which are useful to identify compounds that can prevent, slow or reverse the deposition or accumulation of amyloid. Identification of such compounds could provide potential therapeutics for amyloidosis.
The present invention is directed at providing a method of identifying compounds which prevent or impair the initiation of amyloid deposition and to slow down and reverse the accumulation of amyloid in amyloid deposits. According to the present invention, an assay is provided which can be used to identify compounds which lower the affinity of amyloids and/or amyloid precursor proteins to each other and to nonamyloid proteins or proteoglycans associated with amyloid deposition. Compounds identified by the present invention can be useful in the treatment of patients suffering from primary amyloidosis as well as patients who are suffering secondary amyloidosis in association with another disease because they can interfere with critical events necessary for amyloid deposition, specifically the nucleation events of amyloid protein binding to extracellular matrix proteins (EMP). The present invention provides a method useful in the discovery of drugs for the prevention and treatment of amyloidosis, amyloidosis-related diseases and for the prevention and treatment of tissue destruction associated with amyloid accumulation by providing a method of identifying compounds which impair the binding interactions.
In some cases, such as Alzheimer's disease (AD), the treatment of the amyloidosis secondary to the disease can be useful in improving the prognosis of the patient by counteracting secondary effects of primary disease itself. Accordingly, the present invention provides a method which can identify compounds useful in the treatment of Alzheimer's disease.
According to the present invention, a method is provided which can evaluate a compound's ability to lower the affinity of Alzheimer's amyloid precursor protein (AAP) to proteins or proteoglycans found in the extracellular matrix of brain tissue. By providing a method of identifying compounds which affect the binding of AAP to EMP, the present invention is useful in identifying compounds which can prevent or impair the nucleation of amyloid. Thus, compounds can be identified which specifically affect an event linked with the onset of a pathological condition associated with Alzheimer's disease. By specifically modulating the affinity between AAP and EMP, the binding of AAP to EMP can be reduced or inhibited and formation of amyloid deposits which are commonly found in patients with Alzheimer's disease can be avoided.